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Posttraumatic stress disorder: From pathophysiology to pharmacology

Current Psychiatry. 2020 May;19(5):33-39
May 1, 2020|Psychiatry
Bilge Togay, MD;Rif S. El-Mallakh, MD
Author and Disclosure Information

Dr. Togay is a Visiting Researcher, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky. Dr. El-Mallakh is Professor and Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky.

Disclosures
Dr. Togay is a speaker for Lundbeck, Janssen, Otsuka, Indivior, Sage, Teva, and Takeda. Dr. El-Mallakh is a speaker for Lundbeck, Janssen, Otsuka, Indivior, Sage, Teva, and Takeda.

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,70 but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.71 Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.61 Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.72

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.73

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

  • North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
  • Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

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